TWI225051B - Substituted benzylthiazolidine-2,4-dione derivatives - Google Patents

Abstract

Substituted benzylthiazolidine-2,4-dione derivatives of the formula (I), [wherein A is pyridyl group and cyclohexyl group], or the pharmaceutically acceptable salts and the hydrates thereof, and the process for the preparation thereof are disclosed. These compounds can bond with the receptor as the ligand of PPAR to activate and have the blood sugar reducing effect and lipid reducing effect.

Description

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1225051 A7 B7___ V. Description of the Invention (Technical Field) The present invention relates to a peroxisome proliferator drug receptor (PPAR) agonist, which is a nuclear receptor, especially Human PPAR agonist is a substituted benzylthiazolidine-2,4-dione derivative and its addition salt effective for the prevention and / or treatment of metabolic diseases such as diabetes and hyperlipidemia, its preparation method and its pharmaceutical composition Thing. BACKGROUND OF THE INVENTION Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that belong to the nuclear receptor superfamily, like steroid receptors, lecithin-like receptors, or adenosine-like receptors. So far, three isoforms (α-type, β-type (or 5) -type, and r-type) with different tissue distributions have been identified in humans and various animals (proc. Natl. Acad. Sci ·, 1 992, 89, 46 5 3) . Among them, PPARa is distributed in the liver or kidney with high fatty acid dissimilation ability, especially found in the liver (Endocrinology, 195, 137, 3 5 4). Genes related to fatty acid metabolism and intracellular transport (such as hydrazone) The performance of CoA synthetic enzymes, fatty acid binding proteins and lipoprotein lipases), and apoprotein (AI, All, CIII) genes related to the metabolism of cholesterol and neutral lipids are controlled positively or negatively. PPAR β is commonly found in various tissues in vivo, centering on nerve cells. The physiological significance of PPRAP is still unknown. PPRA r is highly found in adipocytes, and is related to the differentiation of adipocytes (J. Lippid. Res., 1 996, 37, 907). In this way, the various isoforms of PPAR have specific functions in specific organs or tissues. Also, the stunned mice of PPARa showed hyperneutral lipidemia with the increase. The paper size of the paper applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------, ----- ----------- Order --------- line (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 1225051 A7 ___B7 V. Description of the invention () Obesity mainly caused by the increase of white fat cells (J. Biol. Chem., 1 99 8, 2 7 3, 29 5 7 7), strongly suggesting the activation of PPARa and blood lipids (cholesterol And neutral lipids). In other respects, cellulose ester-based drugs and statin-based drugs have been widely used in the treatment of hyperlipidemia. However, cellulose ester drugs have a weak cholesterol-lowering effect, while statins have a weak effect on reducing free fatty acids or triglycerides. In addition, cellulose ester drugs have reported various side effects such as gastrointestinal disorders, rash, headache, liver dysfunction, renal dysfunction, and gallstones. Cellulose ester drugs have a wide range of pharmacological effects as their possible causes. It is also a series of drugs for the treatment of type II diabetes (non-insulin-dependent diabetes mellitus), and has a series of thiazolide-2,4-dione derivatives such as doxoridazine, which have hypoglycemic effect and improvement of hyperinsulinemia The main cell internal standard protein of Pioclazine and Pyroglydazine is PPAR τ, and these pharmacology will increase the transcriptional activation of PPAR r (Endocrinology, 1 996, 137, 4189, Cell., 1995, 83, 803, Cell ., 1995, 83, 813,). Therefore, PPAR r activators (agonists) that increase the transcriptional activation of PPAR r are extremely important as hypoglycemic agents. In this way, considering the function of PPAR transcription factors on adipocytes and the role of regulating mechanisms of glucose metabolism and lipid metabolism, if it can create compounds that activate PPAR by directly binding PPAR, especially human PPAR ligands, it can be expected to have a reason Medical use of compounds with extremely specific mechanisms for lowering blood glucose and / or lowering blood lipids (both cholesterol and neutral lipids). As a ligand of PPARa, it has an affinity compound for PPARa. Except for peanuts, the paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm), --------------- -Order --------- line (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1225051 A7 B7 V. Description of the invention () Tetraenoic acid metabolites In addition to LTB4, the arachidic acids of the HETE (hydroxyarachidonic acid) and HEPE (hydroxyarachidonic acid) groups produced by the oxidation of cytochrome P-450, especially 8-HETE, 8-HEPE, etc. ( Proc. Natl · Acad. S ci., 1 9 9 7, 9 4, 3 1 2). However, these endogenous unsaturated fatty acid derivatives are unstable in metabolism and chemistry and cannot be used as medicine. In addition, reports of serious side effects on the liver have occasionally occurred in doroclida. Therefore, the development of an effective and safe type I diabetes treatment is required. As for the similar structures of the substituted benzylthiazolidine-2,4-dione derivatives of the present invention, JP-A-Sho 5 5-2 26 3 6, JP-A-Sho 60-5 1 1 89, JP-A 61 -85372, JP-A 61-286376, JP-A 1-131169, JP-A 2-83384, JP-A 5-213913, JP-A 8-333355, JP-A 9- 4 8 7 7 1 and JP-A 9-1 6 9 7 4 6, European Patent Publication No. 0 4 4 1 6 0 5, WO-9 2/0 7 8 3 9 and other thiazolidine-2,4-dione derivatives. However, these compounds are thiazolidine-2,4-dione derivatives having different structures from the compounds of the present invention. The patents related to reports of PPAR α agonistic effects include WO-9 7/2 5 04 2 and WO-97/36579, etc., but these compounds have different structures from the compounds of the present invention, and the transcriptional activation of PPAR α Non-satisfactory strength. Hyperlipidemia and diabetes are risk factors for arteriosclerosis. From the prevention of arteriosclerotic diseases, especially coronary arteriosclerosis, it is clinically hopeful to develop effective and safe therapeutic drugs for metabolic diseases. Disclosure of the invention The inventor created an effective and safe structure for the treatment of metabolic diseases. The paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ------, ------ i .— ^ ---- Order --------- line (Please read the precautions on the back before filling this page) 1225051

V. Description of the invention () The new drug, focusing on the specific roles of PPAR lipid metabolism and adipocyte differentiation, conducted repeated and thorough investigations, and found that the following formula (1) was substituted for the lower thiazolidine-2,4-dione The derivative has PPAR transcription activity, hypoglycemic effect, lipid-lowering effect, and finally completes the present invention. The present invention provides a substituted benzylthiazolidine-2,4-dione derivative of the following formula (1), a pharmaceutically acceptable salt thereof, and a hydrate thereof:

[In the formula, A is 卩 ratio [I fixed base and cyclohexyl]. The salt of the compound of the formula (1) of the present invention is a conventional metal salt, such as a salt of an alkali metal (such as sodium, potassium, etc.), a salt of an alkaline earth metal (such as calcium, magnesium, etc.), and a pharmacologically acceptable salt such as aluminum. The substance (1 structure is different from the light of the science of light, and the content of the pyrazolothiazyl base is sometimes mixed with the cyclic ketone, the two are included in the 4-, including the 2. It is also mixed with other materials and the structure is different. This is the case when there are different types of existing things, such as daggers. 内 合 化 围} The formula of Fan 1 is ------ · ------ I --- ^ --- -Order --------- line (please read the notes on the back before filling this page) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Employee Consumer Cooperatives This paper is sized to the Chinese National Standard (CNS) A4 (210 X 297) > = 01225051 A7 B7

> == 〇

/ V-OH

s > = o — > a ^ n Ν Η H first project MeO

> -〇 5. Description of the invention ()

S

N

[Wherein A is pyridyl and cyclohexyl]. The xa isomers and mixtures thereof in the above formula (1) are also included in the scope of the present invention. The compound of formula (1) of the present invention can be produced according to the following method (Scheme n 0

Scheme 1 That is, the compound of the formula (1) can be known from (KOKAI 8-3 3 3 3 5 5) compound (2) and -------- I Γ I L ---- order ------ --- line (please read the precautions on the back before filling this page) The printed version of the employee consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs will be made in the printed format \ — / 程 Η1 第 / (\ 应 反 物 合 化

A i ⑶ The base hexyl ring and base pyrimidine are A Chinese formulas. The biogenic properties should be reversed or converted. The first paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1225051 A7 _ B7 V. Description of the invention () 〇 “Reactive derivatives of carboxyl group” can be chloro chloride, fluorene bromide, anhydride, carbonyl imidazole, etc. When using a reactive derivative, with or without a base in solvents such as dioxane, N, N-dimethylformamide and the like, alkali metal hydrides such as NaH, alkali metal hydroxides such as NaOH, and alkali metals such as potassium carbonate It is carried out in the presence of carbonates, organic bases such as pyridine and triethylamine. When reacting with a carboxylic acid, it is usually carried out in the presence of a condensing agent in a solvent such as dichloromethane, chloroform, and dioxane'N, N-dimethylformamide, with or without alkali and or additives. The condensing agent may be dicyclohexylcarbodiimide, 1-[3- (dimethylamino) propyl] -3 -ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphine Nitrogen, carbonyldiimidazole, etc. The base may be an alkali metal hydroxide such as NaOH, an alkali metal carbonate such as potassium carbonate, or an organic base such as pyridine or triethylamine. The additives may be N-hydroxybenzotriazole, N-hydroxydibutanediimine, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotrifluorene, and the like. The reaction temperature is -20 ~ 100 ° C, preferably about 0 ~ 50oC. The dosage form of the novel compound of the present invention may be tablets, capsules, granules, powders, inhalants or syrups, etc. for oral administration or parenteral for injections, boluses. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be specifically described with reference to the following examples, but the present invention is not limited thereto. Example 1 N-[(2-pyridyl) methyl] -5-[(2,4-dioxothiazol-5-yl) methyl] -2-methoxymethoxyamide This paper is applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) ------------------ *-Order --------- Line (Please read the back first Please fill in this page again) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 1225051 A7 B7 V. Description of the invention () Mixed 5-[(2, 4-dioxothiazol-5-yl) methyl] -2 -Methoxybenzoic acid (282 mg, 1,000 mmol), 2-methyl tfttl amine (114 mg, 1.05 mmol), 1- [3- (dimethylamino) propyl] -3 -ethylcarbodicarbonate The imine hydrochloride (230 mg, 1.20 mmol) and N, N-dimethylformamide (5 ml) were stirred at room temperature for 5.5 hours. After standing overnight, it was acidified by adding water, extracted with ethyl acetate and dried, and recrystallized from acetonitrile to obtain 73.7 mg (20%) of the target substance as colorless crystals. Melting point: 196.0 to 197. (TC; mass analysis 値 m / z 371 (M +); elemental analysis 値 (%) c18h17n3o4s: calculated 値 (%) C, 58.21; H, 4,61; N, 11.31. %, C, 57.98; H, 4.56; N, 11.40. Examples 2 to 4 The following compound was obtained by following the same procedure as in Example 1. Example 2 N-[(3-pyridyl) methyl]- 5-[(2,4-dioxothiazol-5-yl) methylb-methoxybenzylamine melting point 225.0 ~ 226.0 ° C; mass analysis 値 m / z 371 (M +); elemental analysis 値(%) C18H17N304S: Calculated 値 (%) C, 58.21; Η, 4.61; N, 11.31. Measured 値 (%) C, 58.29; Η, 4.57; Ν, 11.44 · Example 3 Ν- [(4-pyridyl) methyl] -5-[(2,4-dioxothiazol-5-yl) methyl] · This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ) ---------------------- Order --------- line (Please read the precautions on the back before filling in this page) Ministry of Economy Wisdom Printed by the Consumer Cooperative of the Property Bureau 1225051 A7 ___ B7 V. Description of the invention () 2-Methoxybenzamine melting point 214,0 ~ 215.0 ° C; Mass analysis 値 m / z 371 (M +); Elemental analysis 値 （ %) C18h17n3o4s: Calculate 値 (% ) C, 58.21; Rhenium, 4.61; N, 11.31 · (tested) Rhenium (%) C, 58.08; Rhenium, 4.59; Ν, 11.38 · Example 4 Ν- (cyclohexylmethyl) -5- [(2,4-Dioxothiazol-5-yl) methyl] methoxybenzylamine Melting point 181.0 to 182.0 ° C; Mass analysis 値 m / z 376 (M +); Elemental analysis 値 (%) C19p24N204S ·· Calculate 値 (%) C, 60,62; Η, 6.43; Measured 値 (%) C, 60.61; Η, 6.41; Ν, 7.49 · Biological activity test Example 1: Activated receptors α and 7 & transcriptional activation test on peroxisome proliferators CH0 cells cultured in Ham's F-12 medium containing 10% of bovine fetal blood sacrifice with free fatty acids removed. Receptor plastids and communication plastids (STRATAGENE) and internal standards for fusion protein expression of fusion proteins in the DNA-binding domain of transcription factors and human-type PPARa and τ ligand binding domains (Biochemistry, 1993, 32, 5598) / 3- Galactosidase (Promega) will be detected after co-transfection with lipamine in a blood free state. -10- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ---- --------- i — ^ ---- Order-- ------- line (please read the notes on the back before filling this page) 1225051 A7 a B7 V. Description of the invention () (Please read the notes on the back before filling this page) Compounds and control compounds ( The control drug of PPAR r was treated with doroclidzone and piocredone. The control drug of PPARa was dissolved in (8S) -HETE) in DMSO and adjusted with Ham's F-12 medium containing 10% bovine fetal blood cymbal with free fatty acids removed. Cultivate until the final concentration of DMSO is 0.01%. After 24 hours, CAT activity and 0-galactosidase activity were measured. The results are shown in Table 1. It can be seen that the compounds of the present invention have strong transcriptional activation effects on peroxisome proliferator-activated receptors α and r. Table 1 Example Transcriptional activation PPARa PPARr EC50 (fiwio 1/1) EC50 (μίΛ〇Ι / Ι) 1 0.353 0.30 2 0.42 96. 0.33 0.235 0.14 4 0.30 0.23 more Rockley Dazong 1.15 p. Oakley Dazong 1.72 (8S) -HETE 1.30 — The possibility of use in the printing industry by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, as described above, the substituted benzylthiazolidine of the present invention 2, 4 -Diketone derivative-1 1-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 1225051 A7 _____B7_ V. Description of the invention () is a novel compound with excellent PPAR transcriptional activation . These compounds of the present invention are effective as a combination of the aforementioned hypoglycemic agents and therapeutic agents for hyperlipidemia because of their agonistic activity against human PPAR. ------'- · --------- ^ ---- Order --------- line AW. (Please read the notes on the back before filling this page) Economy Printed by the Ministry of Intellectual Property Bureau's Consumer Cooperatives • 12- This paper size applies to China National Standard (CNS) A4 (210 X 297 meals)

Claims (1)

1225051 ————-----— Announcement 1 ^ ........ One --- VI. Patent Application Supplement No. 891 1 6994 "Substituted Benzylthiazolidine 2,4-Di "Ketone derivative" patent (revised on September 10, 1993) Six applications for patent scope: 1. A substituted benzylthiazolidine-2,4-dione derivative of the following formula (1) and a pharmaceutically acceptable salt thereof, [Wherein A is pyridyl and cyclohexyl]. 2. The substituted benzylthiazolidine-2,4-dione derivative as described in item 1 of the scope of the patent application, and its ligurol salt, where A is 2-pyridyl. 3. The substituted benzylthiazolidine-2,0 dione derivative and its pharmaceutically acceptable salt as described in the first item of the patent application, wherein A is cyclohexyl. 4. A pharmaceutical composition for lowering blood sugar, containing at least one or more of the substituted benzylthiazolidine-2,4-one derivatives and pharmaceutically acceptable salts thereof as an active ingredient of the following formula (1): [Wherein A is pyridyl and cyclohexyl]. 5 · —A pharmaceutical composition for lowering blood lipids, which contains the following formula (丨) substituted benzyl 1225051 6. Scope of patent application At least one or more of the thiazolidine-2,4-diketone derivatives and their pharmaceutically acceptable salts are active ingredients:. 0Η _MeO 'v 0 hi [wherein A is pyridyl and cyclohexyl]. 6. A pharmaceutical composition for peroxisome proliferator-activated receptor agonism (PPAR) containing the following formula (1) substituted benzylthiazolidine-2,4-dione derivatives and their pharmaceutically acceptable salts At least one of them is an active ingredient [Wherein A is pyridyl and cyclohexyl].